Project 1 will focus on bringing basic science investigation and discovery from the laboratory into the clinic early in this Program Project Grant. As such, the Specific Aims (SA) of Project 1 involve both pre-clinical animal models and early Phase I clinical studies. The central hypothesis of this proposal is that modulation of innate immune effector cells such as monocytes and natural killer (NK) cells can significantly impaet on the efficacy of biologic therapy for cancer prevention and treatment. We have recently demonstrated that the ligand for receptor tyrosine kinase fit3 and the ligands for the hematopoietin IL-2/15 receptor complex act in synergy during the induction of NK cell differentiation from hematopoietic progenitor cells. In SA 1 we will evaluate the efficacy of fit3 ligand plus IL-2 in vivo in pre-clinical and a Phase I clinical trial for patients with acquired immune deficiency. We have in vivo pre-clinical data demonstrating efficacy of the anti-CD20 antibody rituximab and IL-2 in treating malignant human lymphoproliferation, compared with either biologic agent alone. SA 2 will therefore test this combination in Phase I (ongoing) and Phase II (planned) clinical trials for relapsed non-Hodgkin's lymphoma. We have both in vitro and in vivo data demonstrating that pro-inflammatory cytokines are released with the infusion of rituximab and Campath therapy, but the significance of these factors on tumor susceptibility to antibody-mediated apoptosis is unknown. In SA 3, we will perform a Phase I trial administering soluble TNF receptor with rituximab (and then Campath) therapy to assess its effects on host immunity and anti-tumor efficacy. Finally, in SA 4 we will continue to pursue mechanism and modulation of the innate immune response to human malignancy in our chimeric SCID-human mouse model. The immediate goal is to better understand the role of Fc7 receptors expressed on human monocytes and NK cells in mediating the rituximab/IL-2 efficacy against human malignant lymphoproliferation. Collectively, this project should provide an immediate venue by which to translate basic innate immune system discovery into hypothesis -driven pre-elinical and clinical immune therapies for cancer prevention and cancer treatment.